Cannabinoid system and cyclooxygenases inhibitors.

Rationale. The cannabinoid system consists of a complex array of receptors, substances with agonist/antagonist properties for those receptors, biosynthetic machineries and mechanisms for cellular uptake and degradation for endocannabinoids. This system is in interrelation with other systems that comprise lipid mediators like prostaglandins/leukotrienes systems. A clear antagonist, additive or synergic effect of nonsteroidal anti–inflammatory drugs (NSAIDs)–cannabinoid associations was not yet demonstrated. Aim. The present study tried to summarize the existent data on NSAIDS-cannabinoid system interactions. Methods and results A bibliographic research in Medline, Scirus, Embase was made using as keywords cannabinoid, nonsteroidal anti–inflammatory drugs, aspirin, ibuprofen, flurbiprofen, diclofenac, indomethacin, acetaminophen, coxibs, antinociceptive, antinociception, analgesia DiscussionsA systematization of the results focusing on the NSAIDs drugs interaction with the cannabinoid system was presented. Out of all the substances analyzed in the present review, acetaminophen was studied the most regarding its interferences with the cannabinoid system, mainly due to contradictory results. Conclusions Some NSAIDs have additional influences on the cannabinoid system either by inhibiting fatty acid amide hydrolase (FAAH) or by inhibiting a possible intracellular transporter of endocannabinoids. All the NSAIDs that inhibit COX2 can influence the cannabinoid system because a possible important degradative pathway for anandamide and 2–arachidonoyl glycerol might involve COX 2. One of the causes for the variety of experimental results presented might be due to pharmacokinetic mechanisms, depending on the route of administration and the dose Abbreviationsdelta9 THC, (–)–(6aR,10aR)–6,6,9–trimethyl–3–pentyl–6a,7,8,10a–tetrahydro–6H–benzo[c]chromen–1–ol; delta9–THC–11–oic acid, 1–hydroxy–6,6–dimethyl–3–pentyl–6a,7,8,10a–tetrahydrobenzo[c] chromene–9–carboxylic acid; Anandamide, (5Z,8Z,11Z,14Z)–N–(2–hydroxyethyl)icosa–5,8,11,14–tetraenamide; Methanandamide, (5Z,8Z,11Z,14Z)–N–[(2R)–1–hydroxypropan–2–yl]–icosa–5,8,11,14–tetraenamide; 2–AG, 1,3–Dihydroxy–2–propanyl (5Z,8Z,11Z,14Z)–5,8,11,14–eicosatetraenoate; HU 210, (6aR,10aR)– 9–(Hydroxymethyl)–6,6–dimethyl–3–(2–methyloctan–2–yl)–6a,7,10,10a–tetrahydrobenzo [c]chromen–1–ol; SR141716A, 5–(4–Chlorophenyl)–1–(2,4–dichloro–phenyl)–4–methyl–N–(piperidin–1–yl)–1H–pyrazole–3–carboxamide; SR144528, N–[(1S)–endo–1,3,3–trimethyl bicyclo [2.2.1] heptan–2–yl]–5–(4–chloro–3–methylphenyl)–1–(4–methylbenzyl)–pyrazole–3–carboxamide; AM251, 1–(2,4–dichlorophenyl)–5–(4–iodophenyl)–4–methyl–N–(1–piperidyl)pyrazole–3–carboxamide; AM 404, (5Z,8Z,11Z,14Z)–N–(4–hydroxyphenyl)icosa–5,8,11,14–tetraenamide; WIN 55,212–2, (R)–(+)–[2,3–Dihydro–5–methyl– 3–(4–morpholinylmethyl)pyrrolo [1,2,3–de]–1,4–benzoxazin–6–yl]–1–napthalenylmethanone; AM 281, N–(morpholin–4–yl)–5–(4–iodophenyl)–1–(2,4–dichlorphenyl)–4–methyl–1H–pyrazole–3–carboxamide; AM 630, [6–Iodo–2–methyl–1–[2–(4–morpholinyl)ethyl]–1H–indol–3–yl](4–methoxyphenyl)methanone; Ibu Am–5, N–(3–methylpyridin–2–yl)–2–(4'–isobutylphenyl)propionamide; CP 55, 940, 2–[(1R,2R,5R)–5–hydroxy–2–(3–hydroxypropyl) cyclohexyl]–5–(2–methyloctan–2–yl)phenol; NS–398, N–[2–(Cyclohexyloxy)–4–nitrophenyl]methanesulfonamide; SC–560, 5–(4–chlorophenyl)–1–(4–methoxyphenyl)–3–trifluoromethylpyrazole; AM 1241, (3–iodo–5–nitrophenyl)–[1–[(1–methylpiperidin–2–yl)methyl]indol–3–yl]methanone; Met F AEA, 2–methyl–arachidonyl–2'–fluoro–ethylamide; PMSF, Phenylmethylsulfonyl fluoride; URB 597, [3–(3–carbamoylphenyl)phenyl] N–cyclohexylcarbamate; TRPV1, Transient receptor potential vanilloid type 1; CGRP, Calcitonin gene related peptide; COX1, cyclooxygenase type 1; COX2, cyclooxygenase type 2; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; FAAH, fatty acid amide hydrolase; NSAIDs, nonsteroidal anti–inflammatory drugs; p.o., per os; i.p., intraperitoneally; i.th., intrathecally; s.c. subcutaneously; i.pl., intraplantar; i.v., intravenously; CB cannabinoid.


Introduction
Only in 1964 when Ganoi and Mechoulam identified ∆9 tetrahydrocannabinol (∆9 THC) being the main psychotropic agent from Cannabis sativa the researches in the "field" of cannabinoids gain scale. Many efforts to discover the substrate of psychotropic and analgesic effects of ∆9 THC were made. The discovery of cannabinoid receptors and endogenous cannabinoids (endocannabinoids) came about twenty years later. The two main endocannabinoids discovered were, in order, anandamide (arachidonoyl ethanolamine) and 2arachidonoyl glycerol.
Cannabinoid system consists of a complex array of receptors, substances with agonist/antagonist properties for those receptors, biosynthetic machineries and mechanisms for cellular uptake and degradation for endocannabinoids. It might represent a new target for drugs that produce analgesia, attenuation of nausea and vomiting in cancer chemotherapy, reduction of intraocular pressure, appetite stimulation in wasting syndromes, relief from muscle spasms/spasticity in multiple sclerosis and decreased intestinal motility.
The positive effects are often accompanied by adverse reactions like alterations in cognition and memory, dysphoria/euphoria, and sedation [1].
The endocannabinoid system is in interrelation with other systems that comprise lipid mediators like prostaglandins/leukotrienes systems [2]. Nowadays it is well known that cyclooxygenase type 2 (COX2) actions both on arachidonic acid, resulting prostaglandins and other eicosanoids, and on endocannabinoids (anandamide and 2-arachidonoyl glycerol), resulting prostamides and prostaglandin glycerol esters. It is not surprising that these substances have different pharmacological properties than the amides or the esters from which they are derived. From this point of view the inhibition of cyclooxygenases, especially COX2, might have many influences at the level of central nervous system or in immune cells (two of the main domains that are rich in cannabinoid receptors and in cannabinoids). The cyclooxygenase products of endocannabinoids were reviewed elsewhere [3-7] and will not make a subject for this paper.
The cannabinoid receptors and endocannabinoids The human cannabinoid receptor 1 (CB1R) was cloned by Gerrard et al. (1991). CB1 receptors are coupled with Gi/Go proteins and are serpentine receptors. Through G protein action the activity of adenylyl cyclase is diminished, which leads to a decrease of cAMP level. The activity of some ionic channels is also modulated.
The human cannabinoid receptor 2 (CB2R) was first identified in man in 1993.
CB2 receptors are coupled with Gi/Go type proteins. Unlike CB1 receptors, the CB2 ones do not seem to be coupled to ionic channels. They are coupled with intracellular signalization pathways associated to MAP kinase.
Another two serpentine receptors, classified among orphan receptors because, when discovered, there did not exist a specific ligand to bind them, are supposed to be cannabinoid receptors. These two receptors are still named GPR55 and GPR119. Another receptor for anandamide is the transient receptor potential vanilloid1 receptor (TRPV1), the receptor for capsaicin [1].
Anandamide and especially 2-arachidonoyl glycerol can function as retrograde synaptic messengers. They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism [8].
Numerous substances with cannabinoid properties were described. They might act as full or partial agonists, antagonists or inverse agonists, neutral antagonists [9], or may increase the endocannabinoids level (FAAH inhibitors, cellular uptake of cannabinoids inhibitors). Some of them are presented in table I [1].
Cyclooxygenases inhibitors or nonsteroidal antiinflammatory drugs (NSAIDs) are a heterogeneous group of substances that block either the cyclooxygenase site of enzyme cyclooxygenase type 1 or 2 (COX 1 and COX 2, respectively), or its peroxidase site [10,11]. In the first category can be mentioned ibuprofen, diclofenac, indomethacin, coxibs (rofecoxib, celecoxib) and in the second category might be included acetaminophen and metamizole sodium.

Methods
A systematic analysis of data from existing literature databases Medline, Pubmed, Embase, Scirus up to 31.08.2010 was performed. Initial selection of articles was made using as key words cannabinoid AND (nonsteroidal anti-inflammatory drugs OR aspirin OR ibuprofen OR flurbiprofen OR diclofenac OR indomethacin OR acetaminophen OR coxibs) taking into account articles in abstract and full text from clinical and preclinical studies. 225 articles, published after the year © 2011, Carol Davila University Foundation 1972 to date, out of which 199 in full text and 26 in abstract, were found. The search area was reduced by introducing new keywords: antinociceptive OR antinociception OR analgesia. References to all relevant articles were examined to include all relevant reports and review sites on the subject. The study included data in English and French. Following the final selection, 24 items were retained in the study considering the exclusion criteria (analytical interference in the determination of cannabinoids and NSAIDs). The 24 studies that emphasized the interactions between the endocannabinoid system or exogenous cannabinoids and NSAIDs, especially on the analgesic effect, were analyzed in terms of types of cannabinoid receptors or of the endocannabinoids involved. Another aim was to elucidate the mechanism of action of cyclooxygenase inhibitors and their interactions with exogenous cannabinoid agonists.

Results
A systematization of the data found in the articles studied are presented in table 2.

Discussions
We tried to systematize the results presented in the previous table by sorting the anti-inflammatory substances and their interactions with the cannabinoid system.
Indomethacin might interfere with the endocannabinoid system, as reported in some studies made by Burstein SH, et al. 1988 [12], Gühring H, et al. 2001[14], Anikwue R, et al. 2002 [15] and Bujalska M. 2008 [29]. Oral administration of indomethacin decreased the hiperalgesia produced by Δ9-THC -a cannabinoid agonist, but in intrathecal administration did not influence the analgesic effects of HU 210 -another cannabinoid agonist. In chronic oral administration Δ9-THC decreased the effects of indomethacin, possibly by a pharmacokinetic mechanism (Δ9-THC interfered the metabolism of indomethacin). The interference of indomethacin on the cannabinoid system is relatively controversial. Anikwue R, et al. 2002 [15] concluded that indomethacin might not react on the cannabinoid system, while Gühring H, et al. 2001 [14] showed that indomethacin acted by means of the CB receptors. In his study, Bujalska M. 2008 [29] showed that indomethacin might potentiate the low doses of CB1 and CB2 agonists in a neuropathic pain model. Taking into account these studies, we can conclude that indomethacin interfere the cannabinoid system either by the CB receptors or by a pharmacokinetic mechanism.
Some nonselective COX inhibitors, such as sulindac, ketoprofen and naproxen had been tested by Anikwue R, et al. 2002 [15], who showed that these substances did not act directly or indirectly on CB1 or CB2 receptors. On the other hand, aspirin proved to potentiate the effect of HU-210, a CB1 and CB2 receptor agonist (Ruggieri V, et al. 2010, [33]). After Naidu PS, et al. 2009 [31] diclofenac acted synergistically with URB 597 (a potent inhibitor of FAAH).
Out of all the substances included in the NSAIDs group, acetaminophen was studied the most regarding its interferences with the cannabinoid system mainly due to contradictory results. Högestätt ED, et al. 2005 [19] showed that acetaminophen could be transformed in AM 404 in the central nervous system by FAAH. This metabolite is an agonist on TRPV1 receptors, a COX1 and COX2 inhibitor and inhibits the reuptake of anandamide, with an analgesic effect. There are some studies using acute pain models realized on animals performed by Ottani A, et al. 2006 [21] and Mallet C, et al. 2008 [30] and other studies conducted on neuropathic pain models performed by Dani M, et al. 2007 [28]  2. All the NSAIDs that inhibit COX2 can influence the cannabinoid system because a possible important degradative pathway for anandamide and 2-arachidonoyl glycerol might involve COX 2.